Pancreatic cancer is one of the deadliest forms of cancer, with median 5-year survival rates less than 10%. This disease is recalcitrant to chemotherapeutic approaches and recently approved therapies afford only modest improvements in survival. KRAS is the most commonly mutated gene in pancreatic tumors with an incidence rate exceeding 90%. Despite intensive efforts, mutant KRAS (KRASmt) has remained undruggable, hence kinases acting both upstream and downstream of the RAS signaling cascade continue to be exploited for the development of novel agents to attenuate signaling through this critical oncogene. MTX-211 is a first-in- class dual and selective inhibitor of PI3K and EGFR kinase with a promising pharmaceutical profile and ability to prevent reactivation of ERK signaling than ensues from currently approved MEK inhibitor monotherapies. Studies are proposed to optimize single agent activity of MTX-211, our clinical candidate (Aim 1), followed by parallel investigation of two rational combination treatment strategies to further build upon the therapeutic efficacy of MTX-211. Namely, experimental rationale backed by preliminary data support further investigation of MTX-211-based combination regimens that incorporate a MEK inhibitor (Aim 2) or an immune checkpoint inhibitor (Aim 3). Our overall objective is to provide evidence to support clinical development of MTX-211 for the treatment of KRASmt pancreatic cancer. The proposed studies integrate the use of molecular imaging reporters and clinically relevant models of pancreatic cancer to conduct mouse trials that will inform future clinical trial design in a manner which is most likely to impact the management of patients with pancreatic cancer.